ABSTRACT Allergic diseases are some of the most common and most costly illnesses in the United States and the prevalence of allergy has doubled in the last four decades. Mounting evidence from recent epidemiological studies reveals an association between frequent use of the cyclooxygenase (COX) inhibiting drug acetaminophen and increased risk of developing allergic diseases, suggesting a possible role of COX inhibition in causing the allergy epidemic. This possibility is supported by our studies using a mouse model of ovalbumin (OVA)-induced allergic inflammation that reveal COX inhibition augments the allergen-induced inflammation, a Th2 immune response. However, the mechanism by which COX inhibition increases Th2 immunity is not clear. Our preliminary results indicate that COX inhibition during allergic sensitization is sufficient to enhance Th2 immune priming and memory, and that COX inhibition abolishes OVA-specific immune tolerance, suggesting an active role of the COX pathway in the development of Th2 immune responses. Furthermore, COX inhibition strongly augments allergic Th2 responses in a STAT6-independent fashion, suggesting that a non-classical and STAT6-independent Th2 differentiation pathway is strongly activated by COX inhibition. The overall HYPOTHESIS to be evaluated is that COX inhibition augments allergic responses by enhancing dendritic cell immune stimulatory function, increasing memory T cell generation, and suppressing regulatory T cells (Tregs). The SPECIFIC AIMS are: (1) Determine the effect of COX inhibition during allergic sensitization on dendritic cell maturation, differentiation and function. (2) Determine the mechanism by which COX inhibition during allergic sensitization augments STAT6-independent Th2 responses, increases the generation of memory CD4 T cells, and abolishes allergen-specific immunologic tolerance. By defining the cellular and molecular mechanisms for COX inhibition-augmented allergic responses, these studies will advance our understanding of the impact of the COX metabolic pathway on the genesis of adaptive immunity and STAT6- independent Th2 responses, while providing potential targets for early interventions against the development of allergic diseases.